1. Field of the Invention
The present invention relates to a novel useful compound, a use thereof and a preparation method thereof. More particularly, it relates to a novel compound having chemopreventive activity and to a method for preparing the same and a composition comprising the same as an active ingredient.
2. Description of the Prior Art
A living body has functions to excrete xenobiotics by inactivating them or reducing lipophilicity thereof to transform into hydrophilic substances. These functions are performed by mediation of various enzymes and may be classified depending on the kind of enzymes into two groups: Phase I reaction(oxidation, reduction and hydrolysis, etc) and phase II reaction(conjugation). Sometimes, these functions are adversely performed to form a more reactive compound which may cause damages to macromolecules in the cells, thus inducing cancer formation.
Particularly, cytochromes P-450(CYP 450), which are present in smooth endoplasmic reticulum of hepatic cells and other cells, are an oxidation enzymes involved in phase I reaction. Cytochromes P-450 oxidize steroids, fatty acids and amines which are synthesized in a living body as well as metabolize medicines, chemical carcinogens and mutagens to more hydrophilic execretable substances.. Nevertheless, cytochromes P-450 sometimes activate xenobiotics, which causes damages to macromolecules and consequently induce a cancer formation(Black, S. D., Coon, M. J., P-450 cytochromes: Structure and function, Adv. Enzymol., 60:35-87(1987)). Cytochromes P450 are classified into gene families and sub families depending on the similarity of base sequence. Among the multiple forms of P-450, cytochrome P-450 2E1 has a very high substrate specificity to a wide spectrum of exogenous substances and enhances the toxicity of the exogenous substances by activating them.
For example, therapeutically effective dose of acetaminophen causes hepatotoxicity in a chronic alcoholics, because cytochrome P-450 2E1 activate acetaminophen with a high substrate specificity and the activated acetaminophen attacks macromolecules such as proteins to cause hepatic necrosis(Wrighton, S. A., Thomas, P. E., Molowa, D. T., Haniu, M, Guzelian P. S., Characterization of ethanol-inducible human liver N-nitrosodimethylamine demethylase, Biochemistry, 25; 6731-6735(1986)).
For the metabolism of carbon tetrachloride which cause hepatic necrosis, it is reported that an increase in the level of reactive metabolites is closely related to an increase of expression of cytochrome P-450 2E1 (Ansher, S. S. Dolan, P., Bueding E., Chemoprotective effects of two dithiolthiones and butylhydroxyanisole against carbon tertrachloride and acetaminophen toxicity, Hepatoloty, 3; 932-935(1983)). It also plays an important role in activating xenobiotics due to a high affinity to nitrosamine, a precursor carcinogen(Peng, R., Yang, C. S., The induction and competitive inhibition of a high affinity microsomal nitrosodimethylamine demethylase by ethanol, Carcinogenesis, 3; 1457-1461(1982)).
Benzene is known to induce a leucopenia, a leukemia and an agranulocytic anemia and it has been reported that cytochrome P-450 2E1 is involved in the metabolism of benzene(Lewis, J. G., Stewart, W., Adams, D. C., Role of oxygen radicals in induction of DNA damage by metabolite of benzene, Cancer Res., 48;4762-4765(1988)). Recently, it has been reported that this enzyme shows a very high substrate specificity to halothane, a inhaling anesthetic so that causes a hepatotoxicity. This is due to the fact that the increased trifluoroacetyl free radicals formed from intermediates form adducts with liver proteins to produce neoantigens(Kenna, J. G., Pohm, L. R., Factors affecting the expression of trifluoroacetylated microsomal protein neoantigen in rats treated with halothane, Drug Metab. Dispos., 18;788-792(1990)).
Moreover, cytochrome P-450 2E1 is closely related to hepatotoxicity enhancements by activating various low molecular weight organic substances such as isoniazid, ethanol, acetone, p-nitrosodimethylamine, nitrosoamine, phenol, pyridine, pyrazole, p-nitrophenol, aniline or diethylether. Cytochrome P-450 2E1 may also be induced by a fasting or diseases such as diabetes.
On the other hand, the enzymes involved in phase II reactions, for example glutathione S-transferase(hereinafter, "GST") and microsomal epoxide hydrolase(hereinafter "mEH") have a role of detoxicating the exogenous toxic substances. These enzymes detoxicate the exogenous toxic substances in various ways, for example a different isoenzymes of GST transfer a thiol group from glutathione to elecrophilic receptors and mEH hydrate oxides. Therefore, an increase in the amount of such enzymes can play an important role in protecting tissues from oxidative damages and environmental stresses(Pickett, C. B., Lu, A. Y. H., Glutathione S-transferase; Gene structure, regulation and biological function, Annu. Rev. Biochem., 58; 743-764(1989) and Seidegrad, J, DePierre, J. W., Microsomal epoxide hydrolase properties, regulation and function, Biochim. Biophys. Acta., 695; 251-270(1983)).
Therefore, a cancer induction and toxicity due to an activation of xenobiotics can be prevented by modulating the metabolism, that is to say by inhibiting the phase I reactions to inhibit a formation of activated toxic intermediates and by enhancing the phase II reactions to promote the excretion of toxic substances. Extensive researches have been made to provide a chemopreventive agent having a metabolism-modulating activity described above. As a result thereof, there are reported some compounds having a chemopreventive activity.
For example, butylhydroxyanisole, a food antioxidant, shows an anti-cancer activity by inducing enzymes involved in phase II reactions(Cha, Y. N., Bueding, E., Effect of 2(3)-tert-butyl-4-hydroxyanisole administration on the activities of several hepatic microsomal and cytoplasmic enzymes in mice, Biochem. Pharmacol., 28;1917-1921(1979)), and butylhydroxytoluene also shows a anti-cancer activity by inducing enzymes involved in phase II reactions(Cha, Y. N., and Heine, H. S., Comparative effects of dietary administration of 2(3)-tert-butyl-4-hydroxyanisole and 3,5-ditert-butyl-4-hydroxytoluene on the several hepatic enzyme activities in mice and rat, Cancer Res., 42; 2609-2615(1982)).
Pyrazine, a component of naturally occurring or synthetic medicines such as pyrazinamide or oltipraz has been reported to have an activity of inducing cytochrome P-450 2E1 , an enzyme involved in phase I reaction as well as GST and mEH, enzymes involved in phase II reaction(Novak, R. F., Kim, S. G., Brooks, S. C., Primiano, T., Slinas, F. and Novak, J. C., Thiazole, pyridazine and pyrazine induction of glutathione S-transferase of rat, Toxicologist, 11;48(1990)). Oltipraz, which contains pyrazine in the molecule, also has an ability of inducing enzymes of phase II reactions so that it can suppress lung and stomach cancers.
However, these substances have an ability to induce enzymes of phase II reactions but not show any inhibition activity against enzymes of phase I reactions.
On the other hand, allysulfide, a component of garlic oil, has been reported to strongly suppress liver and colon cancers by inhibiting the expression of cytochrome P-450 2E1 which activates a precursor carcinogen, nitrosoamine(Brady, J. F., Li, D, Ishzaki, H and Yang, C. S., Effect of diallylsulfide on rat liver microsomal nitrosoamine metabolism and other monooxygenase activities, Cancer Res., 48;5937-5940(1988) and Hayes, M. A., Rushmore, T. H. and Goldberg, M. T., Inhibition of hepatocarcinogenic responses to 1,2-dimethylhydrazine by diallylsulfide, a component of garlic oil, Carcinogenesis, 8;1155-1157(1987)). Moreover, the present inventors have shown that allylsulfide strongly inhibits the expression of cytochrome P-450 2E1 and further completely suppress cytochrome P-450 2E1 induced by the action of pyrazine(Biochemical pharmacology, (submitted) 1993).
However, there is no effective chemopreventive agent which inhibits the phase I reaction enzymes as well as induce the phase II reaction enzymes.
The present inventors made extensive researches to provide a chemopreventive agent which inhibits the expression and activities of the phase I reaction enzymes as well as induce the phase reaction enzymes and restore them from the inhibition by the inhibitory materials such as isoniazid. As results thereof, we accomplished the present invention.